Visualization of ligand-induced transmembrane signaling in the full-length human insulin receptor
| Autor: | Ünal Coskun, Michal Grzybek, Kelly H. Kim, Theresia Gutmann, Thomas Walz |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Insulin Receptor Substrate Proteins Ligands Receptor tyrosine kinase 03 medical and health sciences 0302 clinical medicine Protein Domains Antigens CD Report Insulin receptor substrate Humans Insulin Research Articles biology Cell Membrane Autophosphorylation Cell Biology Receptor Insulin 3. Good health Transmembrane domain Insulin receptor 030104 developmental biology Biochemistry Ectodomain biology.protein Biophysics Signal transduction 030217 neurology & neurosurgery Protein Binding Signal Transduction |
| Zdroj: | The Journal of Cell Biology J. Cell Biol. 217, 1643-1649 (2018) |
| ISSN: | 1540-8140 0021-9525 |
| Popis: | Using single-particle electron microscopy of the human insulin receptor reconstituted into nanosdiscs, Gutmann et al. show that ligand binding induces a conformational rearrangement in the receptor ectodomain that results in the dimerization of the transmembrane domains and receptor activation. Insulin receptor (IR) signaling plays a critical role in the regulation of metabolism and growth in multicellular organisms. IRs are unique among receptor tyrosine kinases in that they exist exclusively as covalent (αβ)2 homodimers at the cell surface. Transmembrane signaling by the IR can therefore not be based on ligand-induced dimerization as such but must involve structural changes within the existing receptor dimer. In this study, using glycosylated full-length human IR reconstituted into lipid nanodiscs, we show by single-particle electron microscopy that insulin binding to the dimeric receptor converts its ectodomain from an inverted U-shaped conformation to a T-shaped conformation. This structural rearrangement of the ectodomain propagates to the transmembrane domains, which are well separated in the inactive conformation but come close together upon insulin binding, facilitating autophosphorylation of the cytoplasmic kinase domains. Graphical Abstract |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|